Ivermectin and the avermectin family, of which ivermectin is a member, is a series of new and very potent antiparasitic agents which are useful against a broad spectrum of endoparasites and ectoparasites in mammals as well as having agricultural uses against various parasites found in and on crops and in soil. Ivermectin is disclosed in U.S. Pat. No. 4,199,569, issued Apr. 22, 1980 to Chabala and Fisher. Ivermectin is a mixture, in the ratio of approximately 80:20 of 22,23-dihydro C-076 Bla and Blb. In administering ivermectin to animals it is most convenient for parenteral formulations to use an aqueous solution. Non-aqueous solutions tend to cause irritation and tissue damage at the injection site; precipitate the active ingredient at the injection site, have higher viscosity and poorer syringability; and generally have a higher cost. Aqueous liquid formulations for oral use are also preferred over non-aqueous formulations because non-aqueous solvents tend to have an unacceptable taste.
Thus, it is desirable to prepare an aqueous liquid formulation of ivermectin. However, ivermectin has very poor solubility in water, at a level of about 0.005 mg per ml at room temperature.
Ivermectin can be solubilized using surface active agents as solubilizers. This results in the formation of micelles, or minute colloidal particles which surround the ivermectin molecule, isolating it from the water, but forming a clear solution in the water. Such a solution does contain sufficient active ingredient in order to prepare liquid formulations, for oral or parenteral use. However, it was discovered that such micelle formulations were unstable and the ivermectin degraded at such a rate as to render the shelf life inadequate for a commercial preparation.
It was unexpectedly discovered during the investigation of this instability that the use of certain cosolvents and/or substrates would reduce the instability and result in an aqueous liquid solution which is suitable for parenteral or oral administration, and which had adequate shelf life such that a viable commercial preparation was afforded.
Ivermectin is a member of a family of compounds identified as avermectins. The basic avermectin compounds are isolated from the fermentation broth of the microorganism Streptomyces avermitilis. Such compounds are described in British Pat. No. 1,573,955. In addition, certain derivatives of these basic fermentation products have been prepared.
Some of the avermectins contain a 22,23-double bond. This may be selectively reduced to prepare the ivermectin compounds discussed above. In addition, the avermectins possess a disaccharide moiety at the 13-position consisting of the .alpha.-L-oleandrosyl-.alpha.-L-oleandrosyl group. One or both of these saccharide groups may be removed as described in U.S. Pat. No. 4,206,205. The thus produced aglycone derivatives have a hydroxy group at the 13-position. This group may be removed to form the 13-deoxy compound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571. On the avermectin compounds and derivatives are several hydroxy groups which may be acylated as described in U.S. Pat. No. 4,201,861.
It is anticipated that the process and formulation of the instant invention can be carried out on the foregoing compounds since all such compounds share to a varying degree, the aqueous instability of the ivermectin compound.
In addition, a series of compounds identified as milbemycin compounds have the same 16 membered macrocyclic ring as do the avermectin compounds, although they do not have the disaccharide moiety and also differ in other substituent groups. These compounds are disclosed in U.S. Pat. No. 3,950,360 and they also would be expected to benefit from the stabilizing effects of the instant process and formulations.